Type 2 Diabetes and Bone Health in Youth

项目摘要 2型糖尿病(T2D)与成人骨骼质量降低和骨折风险增加有关。然而，它 尚不清楚早期发病的T2D是否会对骨积累和强度产生不利影响。确诊的平均年龄 青春期起病的T2D是在青春期中期，可能受青春期胰岛素抵抗的影响 治疗这种疾病。鉴于骨矿物质积累发生在青春期，了解以下情况很重要 早发性糖尿病是否可能干扰足够的骨矿物质积累，以及决定因素。 当务之急是解决这一知识差距，以便我们能够制定干预措施，防止和扭转 潜在的风险因素，特别是儿童时期不良的骨骼健康可能会导致罹患高血压的风险增加 成年后的骨质疏松症和骨折。这项建议的首要目标是改善老年人的骨骼健康 孩子们。这项应用的中心目标是确定青年发病T2D对骨积累的影响， 显微结构和强度，并了解可能导致这些年轻人骨脆性的因素。我们 假设患有T2D的年轻人的高血糖对骨形成有负面影响，并与 骨转换率低，骨量和微结构改变。 为了验证这一假设，我们建议评估体积骨密度、微结构和强度。 通过有限元得出的参数(破坏载荷和刚度)使用高分辨率外周定量 青少年T2D患者的纵向CT(HRpQCT)和骨转换标志物 同样肥胖的年轻人，血糖正常，体重控制正常。我们还将测量骨骼矿物质含量 采用双能X线骨密度仪(DXA)测定骨密度(BMC)和面骨密度(ABMD)。我们将联合起来 通过DXA、胰岛素敏感性和DXA对身体成分进行仔细的代谢表型分析 血糖(口服糖耐量试验，HbA1c)和可能介导糖尿病影响的胃肠激素 骨头。我们将说明影响骨骼健康的重要因素，包括种族、性别、青春期、 体力活动(通过加速度计)和营养状况。 这项研究在阐明高血糖对骨沉积和微结构的影响方面具有创新性。 在仔细考虑糖尿病相关因素的同时，纵向使用HRpQCT (糖尿病病程、治疗)和其他重要协变量。我们预计，我们将确立这一点 患有T2D的青年患者的高血糖对骨转换有不利影响，导致骨摄入量和骨密度降低 与同样肥胖、血糖正常和体重控制正常的青少年相比，患有T2D的青少年的力量。 我们来自R21试点和可行性实验研究的数据将为研究生活方式铺平道路 以血糖为目标的干预措施，以改善青春期的骨吸收，以及2)评估 对患有糖尿病的青年患者进行骨健康药物治疗，以最好地为这些青年的临床管理提供信息。

Project Summary Type 2 diabetes (T2D) is associated with lower bone quality and increased risk of fracture in adults. However, it is not known if early onset T2D has adverse effects on bone accrual and strength. The mean age of diagnosis of youth onset T2D is in mid-adolescence, likely influenced by pubertal insulin resistance in obese youth at risk for the disease. Given that bone mineral accrual is occurring in the adolescent years, it is important to understand whether early onset diabetes may be interfering with adequate bone mineral accrual, and the determining factors. It is imperative to address this knowledge gap so that we can institute interventions to prevent and reverse the underlying risk factors, particularly that adverse bone health in childhood may translate to increased risk for osteoporosis and fractures in adult life. The overarching goal of this proposal is to improve bone health in children. The central objective of this application is to determine the effect of youth onset T2D on bone accrual, microstructure and strength, and to understand the factors that may lead to bone fragility in these youth. We hypothesize that hyperglycemia in youth with T2D has a negative effect on bone formation and is associated with low bone turnover, altered bone accrual and microarchitecture. To test this hypothesis, we propose to evaluate volumetric bone mineral density, microarchitecture and strength by finite-element derived parameters (failure load and stiffness) using high resolution peripheral quantitative computed tomography (HRpQCT), and bone turnover markers longitudinally in youth with T2D compared with equally obese youth with normoglycemia and normal weight controls. We will also measure bone mineral content (BMC) and areal bone mineral density (aBMD) using dual energy X-ray absorptiometry (DXA). We will combine these evaluations with careful metabolic phenotyping of body composition by DXA, insulin sensitivity and glycemia (oral glucose tolerance test, HbA1c) and gut hormones that may mediate the effect of diabetes on bone. We will account for the important modulators of bone health including race-ethnicity, sex, pubertal stage, physical activity (by accelerometry), and nutrition status. The study is innovative in elucidating the effects of hyperglycemia on bone accrual and microstructure longitudinally in the adolescent years using HRpQCT, while carefully considering diabetes related factors (diabetes duration, treatment) and other important covariates. We anticipate that we will establish that hyperglycemia in youth with T2D has an adverse impact on bone turnover resulting in lower bone accrual and strength in youth with T2D compared with equally obese youth with normoglycemia and normal weight controls. Our data from this R21 pilot and feasibility experimental study will pave the way for 1) studying lifestyle interventions that target glycemia to improve bone accretion in adolescence, and 2) evaluation the effects of pharmacotherapy on bone health in youth with diabetes to best inform clinical management of these youth.